Methods of treating gastrointestinal stromal tumors

ABSTRACT

The present disclosure relates to methods of treating gastrointestinal stromal tumors to a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ripretinib or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 17/727,307 filedApr. 22, 2022, which is a continuation of U.S. Ser. No. 17/583,985 filedJan. 25, 2022 which is a continuation of U.S. Ser. No. 17/180,218 filedFeb. 19, 2021, which is a divisional application of U.S. Ser. No.17/028,640 filed Sep. 22, 2020, which is a continuation of InternationalApplication Number PCT/US2020/045876 filed Aug. 12, 2020, which claimspriority to U.S. Ser. No. 62/885,797 filed Aug. 12, 2019, U.S. Ser. No.62/904,198 filed Sep. 23, 2019, U.S. Ser. No. 62/926,281 filed Oct. 25,2019, U.S. Ser. No. 62/936,018 filed Nov. 15, 2019, U.S. Ser. No.62/968,927 Jan. 31, 2020, U.S. Ser. No. 62/968,945 filed Jan. 31, 2020,U.S. Ser. No. 63/023,921 filed May 13, 2020, and U.S. Ser. No.63/023,936 filed May 13, 2020, the contents of each of which areincorporated herein by reference in their entirety.

BACKGROUND

Gastrointestinal stromal tumors (GIST) comprise less than 1% of allgastrointestinal (GI) tumors, but constitute the most common mesenchymaltumors and soft tissue sarcomas of the GI tract. They occur anywherealong the GI tract but are found most often in the stomach (60%) orsmall intestine (30%) and less frequently in the rectum, colon, ormesentery. In the United States, around 3300 to 6000 new cases of GISTare diagnosed each year. The vast majority of cases are sporadic, andolder age is a recognized risk factor. Mutations in KIT andplatelet-derived growth factor receptor-alpha (PDGFRA) are found in over80% of all primary GISTs. Alterations in neurofibromatosis type 1 gene(NF1) and succinate dehydrogenase (SDH) complex (SDHC) genes as well asaltered methylation of SDHC promoter have been described as oncogenicdrivers in GIST without activating mutations in KIT or PDGFRA, and theyhave been linked to familial and heritable syndromes (NF1 andCarney-Stratakis syndrome).

Despite a wide variation in tumor size, location, and histologicsubtypes (spindle cell, epithelioid cells, and mixed type),approximately 85% of all GISTs share oncogenic mutations in 1 of 2receptor tyrosine kinases (TKs): KIT or PDGFRA. Constitutive activationof either of these TKs plays a central role in the oncogenic behavior ofGIST. The early characterization of GIST mutational status is importantin both the localized and metastatic settings to identifyimatinib-resistant mutations (such as some primary KIT exon 17 mutationsor PDGFRA D842V) or mutations that require a higher dose of imatinib.Patients with GIST lacking KIT or PDGFRA mutations usually do notbenefit from imatinib, and standard treatment algorithms mostly do notapply. However, other mutations may be present in these patients, withthe largest group represented by SDH-deficiency frequently associatedwith Carney or Carney-Stratakis-Syndrome. Other subtypes have mutationsin NF1 (usually associated with neurofibromatosis type I) or in BRAF orKRAS. Very recently, casuistic cases of GIST-like tumors harboring NTRKtranslocations have further expanded the spectrum of molecular subtypes.

In the pre-tyrosine kinase inhibitor (TKI) era, GISTs (often categorizedas gastric leiomyosarcomas or leiomyoblastomas) were treated within thesubtype of agnostic sarcoma trials and lacked an effective systemictherapy. However, a deeper understanding of the molecular pathogenesisand driving role of the protooncogenes KIT and PDGFRA has transformedthe treatment of both localized and metastatic diseases. Localized andresectable tumors are treated surgically which remains the mainstay ofcurative therapy for localized disease. Resected high-risk GIST istypically treated with adjuvant imatinib, whereas low-risk GIST ismanaged with surgery alone. Intermediate-risk GIST is managed on aper-case basis. In an advanced/metastatic setting, imatinib 400 mg dailyis approved, with dose escalation to 800 mg at the time of progression,and has been shown to yield dramatic results in disease control.Imatinib-refractory patients are treated with sunitinib as a second-linetherapy and regorafenib as third-line therapy on resistance orintolerance to sunitinib.

At diagnosis, a mutation in the KIT gene occurs in 80% of GISTs and isusually found in exon 11, and less commonly in exon 9. Both mechanismscause ligand-independent receptor activation, which leads touncontrolled cell growth and transformation. Primary mutations affect aloss-of-function mutation in the JM domain and lead to a shift inequilibrium toward a Type I active or on-state conformation of KIT andaway from a Type II inactive or off-state conformation of KIT. Exon 11primary mutations are the most commonly seen in GISTs (around 70% ofcases), and derive significant benefit from treatment with imatinib inboth the adjuvant and metastatic settings, achieving a 2-yearrelapse-free survival of ˜90% in the adjuvant setting, and a medianevent-free survival just under 2 years in the metastatic setting.Primary mutations (in treatment-naive patients) in exon 9 affect theextracellular domain of KIT, mimicking conformational changes induced byligand binding and triggering KIT receptor homodimerization. Thisdimerization leads to the activation of specific intracellular signalingpathways which can lead to cancer cell proliferation, survival, andresistance. Although less common than exon 11 mutations, exon 9mutations (10%-15% of newly diagnosed cases) are most commonly seen inGISTs arising from the small intestine. Unlike exon 11 mutations, theybenefit less from imatinib in both the adjuvant and metastatic settings.

Despite significant improvement in outcomes compared with those in thepre— mutation-driven/TKI therapy era, response to imatinib is notexperienced by all patients, and most patients with GIST will ultimatelydevelop resistance to imatinib, most commonly due to the development ofsecondary mutations in KIT. Secondary resistance mutations usually arisein the catalytic domain of the kinase: 1) at the switch pocket, whichtypically occur in KIT exons 13 and 14 or PDGFRA exons 14 and 15 andsterically disrupt drug binding or conformationally activate KIT, and 2)in the activation loop switch encoded by KIT exons 17 and 18 and PDGFRA18. Activation loop mutations act by shifting the kinase into anactivated Type I or on-state conformation that is less amenable to drugbinding by any of the approved Type II TKIs. Although uncommon inprimary GIST (1%-2% of newly diagnosed cases), mutations in exons 13, 14and 17 are often responsible for acquired imatinib resistance, with exon17 mutations alone accounting for as many as 50% of the acquiredresistance cases to imatinib, and later to sunitinib. A need exists fora TKI that can broadly inhibit clinically relevant KIT and PDGFRAmutations.

SUMMARY

Described herein are methods of treating a gastrointestinal stromaltumor in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of ripretinib or apharmaceutically acceptable salt thereof.

For example, in one embodiment described herein is a method of treatinga patient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100 mg to 300 mg, e.g.,150 mg, of ripretinib daily, wherein the patient's tumor has progressedfrom, or the patient was intolerant to, a previous first lineadministration of imatinib.

For example, in one embodiment described herein is a method of treatinga patient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100 mg to 250 mg, e.g.,150 mg, of ripretinib daily, wherein the patient's tumor has progressedfrom, or the patient was intolerant to, a previous first lineadministration of imatinib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100 mg to 600 mg, e.g.,100 mg to 250 mg, e.g., 150 mg, of ripretinib daily, wherein thepatient's tumor has progressed from, or the patient was intolerant to, aprevious first line administration of imatinib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient one or more tabletscomprising ripretinib, e.g., tablets each comprising 50 mg to 100 mg ofripretinib, daily, wherein the patient's tumor has progressed from, orthe patient was intolerant to, a previous first line administration ofimatinib. In some examples, the tablets comprise 50 mg of ripretinib. Insome embodiments, the tablets comprise 75 mg of ripretinib. In someembodiments, the tablets comprise 100 mg of ripretinib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient one or more tabletscomprising ripretinib, e.g., tablets each comprising 50 mg to 100 mg ofripretinib, daily, wherein the patient's tumor has progressed from, orthe patient was intolerant to, a previous first line administration ofimatinib, a previous second line administration of sunitinib, and aprevious third line administration of regorafenib or wherein the patienthas a documented intolerance to one or more of imatinib, sunitiniband/or regorafenib. In some embodiments, the tablets comprise 50 mg ofripretinib. In some example, the tablets comprise 75 mg of ripretinib.In some example, the tablets comprise 100 mg of ripretinib. In anotherembodiment, described herein is a method of treating a patient sufferingfrom an advanced gastrointestinal stromal tumor, comprising orallyadministering to the patient 100 mg to 250 mg of ripretinib daily, e.g.,150 mg, wherein the patient's tumor has progressed from, or the patientwas intolerant to, a first line administration of imatinib, a secondline administration of sunitinib, and a third line administration ofregorafenib or wherein the patient has a documented intolerance to oneor more of imatinib, sunitinib and/or regorafenib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100 mg to 600 mg ofripretinib daily, e.g., 100 mg to 250 mg, e.g., 100 mg to 500 mg, e.g.,100 mg to 250 mg, e.g., 150 mg, wherein the patient's tumor hasprogressed from, or the patient was intolerant to, a first lineadministration of imatinib, a second line administration of sunitinib,and a third line administration of regorafenib or wherein the patienthas a documented intolerance to one or more of imatinib, sunitiniband/or regorafenib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient to the patient, on adaily basis, one or more tablets each comprising ripretinib, e.g.,tablets each comprising 50 mg to 100 mg of ripretinib, wherein thepatient's tumor has progressed from, or the patient was intolerant to, afirst line administration of imatinib, a second line administration ofsunitinib, and a third line administration of regorafenib or wherein thepatient has a documented intolerance to one or more of imatinib,sunitinib and/or regorafenib. In some embodiment, the tablets comprise50 mg of ripretinib. In some embodiment, the tablets comprise 75 mg ofripretinib. In some embodiment, the tablets comprise 100 mg ofripretinib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100 mg to 600 mg ofripretinib daily, e.g., 100 mg to 250 mg, e.g., 100 mg to 500 mg, e.g.,100 mg to 250 mg, e.g., 150 mg, e.g., 300 mg, wherein the patient waspreviously administered at least two tyrosine kinase inhibitors beforeadministration of the ripretinib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 150 mg of ripretinib oncedaily, wherein the patient was previously administered at least twotyrosine kinase inhibitors before administration of the ripretinib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient, on a daily basis, one ormore tablets each comprising ripretinib, e.g., tablets each comprising50 mg to 100 mg of ripretinib, wherein the patient was previouslyadministered at least two tyrosine kinase inhibitors beforeadministration of the ripretinib. In some embodiment, the tabletscomprise 50 mg of ripretinib. In some embodiment, the tablets comprise75 mg of ripretinib. In some embodiment, the tablets comprise 100 mg ofripretinib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 150 mg of ripretinib oncedaily, wherein the patient was previously administered three or morekinase inhibitors before administration of the ripretinib. In someembodiments, after at least 4 weeks of the daily ripretinibadministration, the patient has at least a 5-month progression-freesurvival as measured using mRECIST v1.1. In some embodiments, orallyadministering to the patient 150 mg of ripretinib once daily comprisesadministering to the patient three tablets each tablet comprising 50 mgof ripretinib. In some embodiments, one of the three or more kinaseinhibitors is imatinib. In some embodiments, the patient was previouslyadministered imatinib, sunitinib and regorafenib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 150 mg daily ripretinib,wherein the patient's tumor has progressed from, or the patient wasintolerant to, a first line administration of imatinib, a second lineadministration of sunitinib, and a third line administration ofregorafenib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 150 mg of ripretinib onceor twice daily, wherein the patient's tumor has progressed from, or thepatient was intolerant to, a previous first line administration ofimatinib.

In another embodiment, described herein is a method for achieving atleast 5 months of progression free survival as determined by mRECIST 1.1in a patient having an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100, 150 200, or 300 mgof ripretinib daily or twice daily for at least 28 days.

In another embodiment, described herein is a method for achieving atleast 5 months of progression free survival as determined by mRECIST 1.1in a patient having an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100, 150, or 200 mg ofripretinib daily or twice daily for at least 28 days.

In another embodiment, descried herein is a method of treating a patientsuffering from Grade 3 palmer-plantar erythrodysesthesia syndrome whilebeing administered 150 mg ripretinib daily or twice daily, comprisingwithholding administration of ripretinib for at least 7 days or untilthe patient has less than or equal to Grade 1 palmer-plantarplantarerythrodysesthesia syndrome, then administering to the patient 100 mgdaily (e.g., 100 mg once daily) ripretinib for at least 28 days.

In another embodiment, descried herein is a method of treating a patientsuffering from Grade 2 palmer-plantar erythrodysesthesia syndrome uponadministration of 150 mg ripretinib daily or twice daily, comprising a)withholding administration of ripretinib until the patient has less thanor equal to Grade 1 palmer-plantar erythrodysesthesia syndrome orbaseline; b) if the patient recovers from the palmer-plantarerythrodysesthesia syndrome within 7 days of withholding administration,then administering to the patient 150 mg daily ripretinib or c) if thepatient has not recovered, then administering to the patient 100 mgdaily ripretinib for at least 28 days.

In another embodiment, described herein is a method of treating agastrointestinal stromal tumor in a patient in need thereof, wherein thepatient is being treated concurrently with a CYP3A4 inhibitor, themethod comprising: orally administering to the patient 100 mg or 150 mgof ripretinib, or a pharmaceutically acceptable salt thereof, once ortwice daily, and wherein upon administration of the ripretinib and theCYP3A4 inhibitor, provides an increased ripretinib area under the plasmaconcentration curve (AUC_(0-inf)) of 80% or more in the patient ascompared to administration of ripretinib without concurrent treatment ofthe CYP3A4 inhibitor, and therefore the patient is at higher risk of anadverse event; and monitoring the patient more frequently, as comparedto a patient not being treated with a CYP3A4 inhibitor, for the adverseevent.

In another embodiment, described herein is a method of treating agastrointestinal stromal tumor in a patient in need thereof, wherein thepatient is being treated concurrently with a proton pump inhibitor, themethod comprising: orally administering to the patient 100 mg or 150 mgof ripretinib, or a pharmaceutically acceptable salt thereof, once ortwice daily, and wherein administration of the ripretinib and protonpump inhibitor to the patient provides no clinically significantdifference in the plasma exposure of ripretinib in the patient ascompared to administration of ripretinib without concurrent treatment ofthe proton pump inhibitor.

In another embodiment, described herein is a method of treating agastrointestinal stromal tumor in a patient in need thereof, the methodcomprising orally administering to the patient 100 mg or 150 mg ofripretinib, or a pharmaceutically acceptable salt thereof, once or twicedaily, wherein the ripretinib is administered to the patient with foodor without food.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a plot of survival probability with respect toprogression-free survival (PFS) for patients on ripretinib and patientson placebo as described in Example 2.

FIG. 2 depicts a plot of survival probability with respect to overallsurvival (OS) for patients on ripretinib and patients on placebo asdescribed in Example 2.

FIG. 3 depicts plots illustrating survival probability with respect toOS in patients on ripretinib, crossed over from placebo to ripretinib,and patients without cross-over.

FIG. 4 depicts PFS by line of therapy for patients with GIST treatedwith 150 mg once daily of ripretinib.

FIG. 5A, FIG. 5B, and FIG. 5C depict patient report outcome by EQ-VASvisual scale (FIG. 5A) and score changes from baseline (FIG. 5B) used toassess these scores and corresponding patient percentage distributions(FIG. 5C) used in the study of Example 2 at 150 mg ripretinib QD. In thestudy, 70 patients were receiving ripretinib and 32 were receivingplacebo.

FIG. 6A, FIG. 6B, and FIG. 6C depict EORTC QLQ-C30 physical functionquestions (FIG. 6A) and patient score changes (FIG. 6B) from baseline inresponse and corresponding patient percentage distributions (FIG. 6C)used in the study of Example 2 at 150 mg ripretinib QD. Physicalfunction scores improved on average 1.6 from baseline to C2D1 amongpatients taking ripretinib in contrast to placebo patients who saw onaverage, a decline from baseline to C2D1 of 8.9 (p=0.004). In thisstudy, 71 patients were receiving ripretinib and 32 were receivingplacebo.

FIG. 7A, FIG. 7B, and FIG. 7C depict EORTC QLQ-C30 role functionquestions (FIG. 7A) and patient score changes (FIG. 7B) from baseline inresponse and corresponding patient percentage distributions (FIG. 7C)used in the study of Example 2 at 150 mg ripretinib QD. In the study, 70patients were receiving ripretinib and 32 were receiving placebo.

FIG. 8A and FIG. 8B depict patient score changes from baseline (FIG. 8A)and percentage distributions (FIG. 8B) in response to Question C29 ofEORTC QLQ-C30 (“How would you rate your overall health during the pastweek?”) from a scale of 1 (“Very poor”) to 7 (“Excellent”) in the studyof Example 2 at 150 mg ripretinib QD. In the study, 70 patients werereceiving ripretinib and 32 were receiving placebo.

FIG. 9A and FIG. 9B depict patient score changes from baseline (FIG. 9A)and corresponding patient percentage distributions (FIG. 9B) in responseto Question C30 of EORTC QLQ-C30 (“How would you rate your overallquality of life during the past week?”) from a scale of 1 (“Very poor”)to 7 (“Excellent”) in the study of Example 2 at 150 mg ripretinib QD. Inthe study, 70 patients were receiving ripretinib and 32 were receivingplacebo.

FIG. 10 depicts mean changes in baseline scores in EQ-VAS across varioustime points, from Cycle 1, Day 15 up to Cycle 15, Day 1 of theintention-to-treat population in the study of Example 2 at 150 mgripretinib QD.

FIG. 11A and FIG. 11B depict mean changes in baseline scores in EORTCQLQ-C30 role function and EORTC QLQ-C30 physical function, respectively,across various time points, from Cycle 1, Day 15 up to Cycle 15, Day 1of the intention-to-treat population in the study of Example 2 at 150 mgripretinib QD.

FIG. 12A and FIG. 12B depict mean changes in baseline scores in EORTCQLQ-C30 question C29 response and EORTC QLQ-C30 question C30 response,respectively, across various time points, from Cycle 1, Day 15 up toCycle 15, Day 1 of the intention-to-treat population in the study ofExample 2 at 150 mg ripretinib QD.

FIG. 13 depicts exemplary PFS data for patients who crossed over fromplacebo to ripretinib in the study described in Example 2 at 150 mgripretinib QD.

FIG. 14A and FIG. 14B depict progression free survival (PFS) studies inthe double-blind and open-label periods in the study of Example 2 forpatients who dose escalated from 150 mg ripretinib QD 150 mg ripretinibBID. FIG. 14C depicting median PFS data and other parameters in thesePFS studies.

FIG. 15 shows exemplary PFS data among patients with wild-type KITmutations in the study of Example 2.

FIGS. 16A and 16B depict Progression free survival (PFS) and overallsurvival (OS) data based on patients with a primary Exon 11 mutation orthose with a non-Exon 11 mutation in the study of Example 2 at 150 mgripretinib QD.

FIGS. 17A and 17B depicts progression free survival (PFS) and overallsurvival (OS) data based on patients with a primary Exon 11 mutation ora primary Exon 9 mutation in the study of Example 2 at 150 mg ripretinibQD.

FIGS. 18A and 18B depicts progression free survival (PFS) and overallsurvival (OS) data based on patients with a primary Exon 11 mutation, ora primary Exon 9 mutation, or another mutation, or wild type (KIT andPDGFRA) in the study of Example 2 at 150 mg ripretinib QD.

FIGS. 19A and 19B depicts progression free survival (PFS) studies forpatients with certain primary mutations (Exon 9 or Exon 11) who doseescalated from 150 mg QD ripretinib to 150 mg BID ripretinib for thedouble-blind and open-label periods, respectively, in the study ofExample 2.

FIG. 20 shows exemplary progression free survival data for patients withother KIT mutations and PGDFR mutations in the study of Example 2 at 150mg ripretinib QD.

FIG. 21 depicts the median first appearance and worst grade of alopeciaand PPES in corresponding patients receiving ripretinib in the studydescribed in Example 2.

FIG. 22A depicts a mean change from baseline for physical functionpatient reported outcome of the EORTC-QLQ-C30 in patients receivingripretinib, with and without alopecia, in the study described in Example2. FIG. 22B depicts a mean change from baseline for role functionpatient reported outcome of the EORTC-QLQ-C30 in patients receivingripretinib, with and without alopecia, in the study described in Example2. FIG. 22C depicts a mean change from baseline for physical functionpatient reported outcome of the EORTC-QLQ-C30 in patients receivingripretinib, with and without palmar-plantar erythrodysesthesia syndrome(PPES), in the study described in Example 2. FIG. 22D depicts a meanchange from baseline for role function patient reported outcome of theEORTC-QLQ-C30 in patients receiving ripretinib, with and withoutpalmar-plantar erythrodysesthesia syndrome (PPES), in the studydescribed in Example 2.

FIG. 23A depicts a mean change from baseline for overall health patientreported outcome of the EORTC-QLQ-C30 in patients receiving ripretinib,with and without alopecia, in the study described in Example 2. FIG. 23Bdepicts a mean change from baseline for overall quality of life patientreported outcome of the EORTC-QLQ-C30 in patients receiving ripretinib,with and without alopecia, in the study described in Example 2. FIG. 23Cdepicts a mean change from baseline for overall health patient reportedoutcome of the EORTC-QLQ-C30 in patients receiving ripretinib, with andwithout palmar-plantar erythrodysesthesia syndrome (PPES), in the studydescribed in Example 2. FIG. 23D depicts a mean change from baseline foroverall quality of life patient reported outcome of the EORTC-QLQ-C30 inpatients receiving ripretinib, with and without palmar-plantarerythrodysesthesia syndrome (PPES), in the study described in Example 2.

FIG. 24A depicts a mean change from baseline for state of health (VAS)patient reported outcome of the EORTC-QLQ-C30 in patients receivingripretinib, with and without alopecia, in the study described in Example2. FIG. 24B depicts a mean change from baseline for state of health(VAS) patient reported outcome of the EORTC-QLQ-C30 in patientsreceiving ripretinib, with and without palmar-plantar erythrodysesthesiasyndrome (PPES), in the study described in Example 2.

FIG. 25A and FIG. 25B depict exemplary PFS of subjects who doseescalated to 150 mg BID, PFS before (PFS1) and after (PFS2) doseescalation.

FIG. 26A-D depicts an exemplary comparison of PFS of patient subgroupswith Exon 9 (FIG. 26A), Exon 11 (FIG. 26B), Exon 13 (FIG. 26C), or Exon17 (FIG. 26D) KIT mutations. This exemplary data show that ripretinibshowed PFS benefit in all assessed patient subgroups compared toplacebo.

FIG. 27 shows PFS data of exemplary second and third-line patients withExons 9, 11, 13, or 17 KIT mutations. The data show that, in second andthird line populations, patients with such various KIT mutations havecomparable PFS.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Certain terms employed in the specification,examples and appended claims are collected here. These definitionsshould be read in light of the remainder of the disclosure and asunderstood by a person of skill in the art. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by a person of ordinary skill in the art.

Definitions

As used herein, “ripretinib” is a compound represented by the followingstructure:

As used herein, “sunitinib” is a compound represented by the followingstructure:

As used herein, “imatinib” is a compound represented by the followingstructure:

As used herein, “regorafenib” is a compound represented by the followingstructure:

As used herein, “Compound A” is a compound represented by the followingstructure:

“Individual,” “patient,” or “subject” are used interchangeably hereinand include any animal, including mammals, including mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and humans. The compounds described herein can be administered to amammal, such as a human, but can also be administered to other mammalssuch as an animal in need of veterinary treatment, e.g., domesticanimals (e.g., dogs, cats, and the like), farm animals (e.g., cows,sheep, pigs, horses, and the like) and laboratory animals (e.g., rats,mice, guinea pigs, and the like). The mammal treated in the methodsdescribed herein is desirably a mammal in which treatment of a disorderdescribed herein is desired, such as a human.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe compositions. Compounds included in the present compositions thatare basic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including, but notlimited to, malate, oxalate, chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

As used herein, “treating” includes any effect, e.g., lessening,reducing, modulating, or eliminating, that results in the improvement ofthe condition, disease, disorder and the like.

Therapeutically effective amount” includes the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. A compound describedherein, e.g., ripretinib is administered in therapeutically effectiveamounts to treat a condition described herein, e.g., gastrointestinalstromal tumors. Alternatively, a therapeutically effective amount of acompound is the quantity required to achieve a desired therapeuticand/or prophylactic effect, such as an amount which results in theprevention of or a decrease in the symptoms associated with thecondition.

As used herein, “AUC_(0-24 h)” refers to the area under the plasmaconcentration-time curve from time zero to 24 hours for a compounddescribed herein. As used herein, “AUC_(0-inf)” refers to the area underthe plasma concentration-time curve from time zero to infinite time fora compound described herein. As used herein, “C_(max)” refers to themaximum plasma concentration of a compound described herein.

A compound described herein, e.g., ripretinib, can be formulated as apharmaceutical composition using a pharmaceutically acceptable carrierand administered by a variety of routes. In some embodiments, suchcompositions are for oral administration. In some embodiments,compositions formulated for oral administration are provided as tablets.In some embodiments, such compositions are for parenteral (by injection)administration (e.g., a composition formulated for local injection atthe site of a tumor, e.g., a diffuse-type giant cell tumor). In someembodiments, such compositions are for transdermal administration. Insome embodiments, such compositions are for topical administration. Insome embodiments, such compositions are for intravenous (IV)administration. In some embodiments, such compositions are forintramuscular (IM) administration. Such pharmaceutical compositions andprocesses for preparing them are well known in the art. See, e.g.,REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al.,eds., 19^(th) ed., Mack Publishing Co., 1995).

Methods of Treatment

Described herein are methods of treating gastrointestinal stromal tumorsin a patient in need thereof. For example, the present disclosurerelates to a method of treating a patient suffering from an advancedgastrointestinal stromal tumor, comprising orally administering to thepatient 100 mg or more of ripretinib daily, e.g., 100 mg to 5000 mg,e.g., 100 mg to 500 mg, 100 mg to 250 mg, e.g., 150 mg, wherein thepatient's tumor has progressed from, or the patient was intolerant to, aprevious first line administration of imatinib. In some embodiments, themethod comprises administering to the patient 110 mg of ripretinibdaily. In some embodiments, the method comprises administering to thepatient 120 mg of ripretinib daily. In some embodiments, the methodcomprises administering to the patient 130 mg of ripretinib daily. Insome embodiments, the method comprises administering to the patient 140mg of ripretinib daily. In some embodiments, the method comprisesadministering to the patient 150 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 200 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 250 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 300 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 350 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 400 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 450 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 500 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 550 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 600 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 650 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 700 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 750 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 800 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 850 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 900 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 950 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 1000 mgof ripretinib daily. In some embodiments, the method comprisesadministering to the patient 150 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 200 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 250 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 300 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 350 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 400 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 450 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 500 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 550 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 600 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 650 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 700 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 750 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 800 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 850 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 900 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 950 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 1000 mgof ripretinib once daily. In some embodiments, the method comprisesadministering to the patient 150 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 200 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 250 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 300 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 350 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 400 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 450 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 500 mg ofripretinib twice daily.

In some embodiments, a patient was only previously treated with a firstline administration of imatinib, e.g., only imatinib and no othertherapeutic compounds had been administered to the patient beforeadministration of ripretinib to the patient. For example, a patient wasnot previously administered with sunitinib and/or regorafenib, e.g., thepatient was not previously given a second line administration ofsunitinib therapy and/or a third-line administration of regorafenibtherapy.

In some embodiments, the patient has a non-nodal tumor lesion of greaterthan or equal to 1.0 cm in the long axis or greater than or equal todouble the slide thickness in the long axis, within 21 days prior to thefirst dose of ripretinib. Contemplated methods of treatment includeadministering ripretinib on a 42-day cycle, comprising dailyadministrations of ripretinib without administering sunitinib. After atleast one 42-day cycle comprising daily administrations of ripretinib,the patient may have progression-free survival as measured using mRECISTv1.1. In some embodiments, the patient treated with dailyadministrations of ripretinib may have significant progression freesurvival (e.g., about 3 months progression free survival or more, e.g.,about 6 months progression free survival, as compared to a second linedaily administration of 50 mg sunitinib for four weeks followed by twoweeks without daily administrations on a 42-day cycle, wherein thepatient's tumor has progressed from, or the patient was intolerant to,the previous first line administration of imatinib.

Contemplated treatments with ripretinib may treat a broad spectrum ofKIT and PDGFRA mutations. For example, a patient's tumor may have a KITexon 9 mutation, a PDGFRA exon 18 mutation, a PDGFRA exon 12 mutation ora PDGFRA exon 18 activation loop mutation. For example, the patient'stumor mutation is a PDGFRA D842V mutation.

In some embodiments, a patient's tumor has an imatinib resistantmutation selected from the group consisting of a KIT exon 17 activationloop mutation, a KIT exon 18 activation loop mutation, a KIT exon 13mutation, a KIT exon 14 mutation, a KIT exon 18 mutation, a PDGFRA exon12 mutation, a PDGFRA exon 14 mutation, a PDGRFA exon 15 mutation, and aPDGFRA exon 18 activation loop mutation. For example, the imatinibresistant mutation is a PDGFRA D842V mutation.

In some embodiments, the patient's tumor has an imatinib resistantmutation selected from the group consisting of KIT exon 13 or 14mutation, PDGFRA exon 14 or 15 mutation, a KIT 17 or 18 activation loopmutation, and a PDGFRA 18 activation loop mutation. For example, thepatient's tumor has an imatinib resistant KIT exon 17 mutation.

Also described herein is a method of treating a patient suffering froman advanced gastrointestinal stromal tumor, comprising orallyadministering to the patient 100 mg or more, e.g., up to about 600 mg,e.g. up to about 250 mg, e.g., 100 mg or 150 mg, of ripretinib daily,wherein the patient's tumor has progressed from, or the patient wasintolerant to, a first line administration of imatinib, a second lineadministration of sunitinib, and a third line administration ofregorafenib or wherein the patient has a documented intolerance to oneor more of imatinib, sunitinib and/or regorafenib. Contemplated methodsof treatment include orally administering 100 mg, 150 mg or more ofripretinib daily without administering sunitinib on a 42-day cycle. Insome embodiments, the method comprises administering to the patient 110mg of ripretinib daily. In some embodiments, the method comprisesadministering to the patient 120 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 130 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 140 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 150 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 200 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 250 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 300 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 350 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 400 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 450 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 500 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 550 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 600 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 650 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 700 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 750 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 800 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 850 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 900 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 950 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 1000 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 150 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 200 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 250 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 300 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 350 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 400 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 450 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 500 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 550 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 600 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 650 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 700 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 750 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 800 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 850 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 900 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 950 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 1000 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 150 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 200 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 250 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 300 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 350 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 400 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 450 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 500 mg of ripretinib twice daily.

In some embodiments, a method of treating a patient suffering from anadvanced gastrointestinal stromal tumor, comprising orally administeringto the patient 100 mg or more of ripretinib daily, e.g., up to about 600mg, e.g., 100 mg to 250 mg, e.g., 100 mg to 500 mg, e.g., 100 mg to 250mg, e.g., 150 mg, wherein the patient was previously administered atleast two tyrosine kinase inhibitors, is contemplated. Contemplatedmethods of treatment include orally administering 100 mg, 150 mg or moreof ripretinib daily without administering sunitinib on a 42-day cycle.In some embodiments, the method comprises administering to the patient110 mg of ripretinib daily. In some embodiments, the method comprisesadministering to the patient 120 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 130 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 140 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 150 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 200 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 250 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 300 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 350 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 400 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 450 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 500 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 550 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 600 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 650 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 700 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 750 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 800 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 850 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 900 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 950 mg ofripretinib daily. In some embodiments, the method comprisesadministering to the patient 1000 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 100 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 150 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 200 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 250 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 300 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 350 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 400 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 450 mg of ripretinib daily. In someembodiments, the method comprises administering to the patient 500 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 550 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 600 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 650 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 700 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 750 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 800 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 850 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 900 mg ofripretinib once daily. In some embodiments, the method comprisesadministering to the patient 950 mg of ripretinib once daily. In someembodiments, the method comprises administering to the patient 1000 mgof ripretinib once daily. In some embodiments, the method comprisesadministering to the patient 150 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 200 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 250 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 300 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 350 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 400 mg ofripretinib twice daily. In some embodiments, the method comprisesadministering to the patient 450 mg of ripretinib twice daily. In someembodiments, the method comprises administering to the patient 500 mg ofripretinib twice daily. In some embodiments, the patient has previouslybeen administered two separate tyrosine kinase inhibitors, each selectedfrom the group consisting of imatinib, sunitinib, regorafenib,lapatinib, gefitinib, erlotinib, vatalanib, crenolanib, andpharmaceutically acceptable salts thereof. In some embodiments, each ofthe tyrosine kinase inhibitors is independently selected from the groupconsisting of imatinib, sunitinib, and regorafenib. In some embodiments,each of the tyrosine kinase inhibitors is independently selected fromthe group consisting of imatinib mesylate, sunitinib malate, andregorafenib.

In some embodiments of the methods described herein, the patient isorally administered one or more tablets comprising ripretinib. Forexample, the disclosed methods include a method of treating a patientsuffering from an advanced gastrointestinal stromal tumor, comprisingorally administering to the patient one or more tablets comprisingripretinib, e.g., tablets each comprising 50 mg to 100 mg of ripretinib,daily, wherein the patient's tumor has progressed from, or the patientwas intolerant to, a previous first line administration of imatinib. Insome embodiments, the patient is administered one tablet comprisingripretinib. In some embodiments, the patient is administered one tabletcomprising 50 mg of ripretinib. In some embodiments, the patient isadministered one tablet comprising 50 mg of ripretinib once daily. Insome embodiments, the patient is administered two tablets eachcomprising 50 mg of ripretinib. In some embodiments, the patient isadministered two tablets each comprising 50 mg of ripretinib once daily.In some embodiments, the patient is administered three tablets eachcomprising 50 mg of ripretinib. In some embodiments, the patient isadministered three tablets each comprising 50 mg of ripretinib oncedaily. In some embodiments, the patient is administered four tabletseach comprising 50 mg of ripretinib. In some embodiments, the patient isadministered four tablets each comprising 50 mg of ripretinib oncedaily. In some embodiments, the patient is administered five tabletseach comprising 50 mg of ripretinib. In some embodiments, the patient isadministered five tablets each comprising 50 mg of ripretinib oncedaily. In some embodiments, the patient is administered six tablets eachcomprising 50 mg of ripretinib. In some embodiments, the patient isadministered six tablets each comprising 50 mg of ripretinib once daily.

Additionally, the disclosed methods include a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient, on a daily basis, one ormore tablets each comprising ripretinib, e.g., tablets each comprising50 mg to 100 mg of ripretinib, wherein the patient's tumor hasprogressed from, or the patient was intolerant to, a first lineadministration of imatinib, a second line administration of sunitinib,and a third line administration of regorafenib or wherein the patienthas a documented intolerance to one or more of imatinib, sunitiniband/or regorafenib. In some embodiments, the patient is administered onetablet comprising ripretinib. In some embodiments, the patient isadministered one tablet comprising 50 mg of ripretinib. In someembodiments, the patient is administered one tablet comprising 50 mg ofripretinib once daily. In some embodiments, the patient is administeredtwo tablets each comprising 50 mg of ripretinib. In some embodiments,the patient is administered, once daily, two tablets each comprising 50mg of ripretinib. In some embodiments, the patient is administered threetablets each comprising 50 mg of ripretinib. In some embodiments, thepatient is administered, once daily, three tablets each comprising 50 mgof ripretinib once daily.

In some embodiments, provided is a method of treating a patientsuffering from an advanced gastrointestinal stromal tumor, comprisingorally administering to the patient, on a daily basis, one or moretablets each comprising ripretinib, e.g., tablets each comprising 50 mgto 100 mg of ripretinib, wherein the patient was previously administeredat least two tyrosine kinase inhibitors before administration of theripretinib. In some embodiments, the patient is administered one tabletcomprising ripretinib. In some embodiments, the patient is administeredone tablet comprising 50 mg of ripretinib. In some embodiments, thepatient is administered one tablet comprising 50 mg of ripretinib oncedaily. In some embodiments, the patient is administered two tablets eachcomprising 50 mg of ripretinib. In some embodiments, the patient isadministered, once daily, two tablets each comprising 50 mg ofripretinib. In some embodiments, the patient is administered threetablets each comprising 50 mg of ripretinib. In some embodiments, thepatient is administered, once daily, three tablets each comprising 50 mgof ripretinib. In some embodiments, the patient has previously beenadministered two separate tyrosine kinase inhibitors, each selected fromthe group consisting of imatinib, sunitinib, regorafenib, lapatinib,gefitinib, erlotinib, vatalanib, crenolanib, and pharmaceuticallyacceptable salts thereof. In some embodiments, each of the tyrosinekinase inhibitors is independently selected from the group consisting ofimatinib, sunitinib, and regorafenib. In some embodiments, each of thetyrosine kinase inhibitors is independently selected from the groupconsisting of imatinib mesylate, sunitinib malate, and regorafenib.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 150 mg of ripretinib oncedaily, wherein the patient was previously administered three or morekinase inhibitors before administration of the ripretinib. In someembodiments, after at least 4 weeks of the daily ripretinibadministration, the patient has at least a 5-month progression-freesurvival as measured using mRECIST v1.1. In some embodiments, orallyadministering to the patient 150 mg of ripretinib once daily comprisesadministering to the patient three tablets each tablet comprising 50 mgof ripretinib. In some embodiments, one of the three or more kinaseinhibitors is imatinib. In some embodiments, the patient was previouslyadministered imatinib, sunitinib and regorafenib.

In some embodiments, if the patient suffers from a Grade 3palmer-plantar erythrodysesthesia syndrome upon administration of theripretinib, the method further comprises a) withholding administrationof ripretinib for at least 7 days or until the patient has less than orequal to Grade 1 palmer-plantar erythrodysesthesia syndrome, thenadministering to the patient 100 mg daily (e.g., 100 mg once daily)ripretinib for at least 28 days.

In some embodiments, if the patient suffers from a Grade 2palmer-plantar erythrodysesthesia syndrome upon administration of theripretinib, the method further comprises: a) withholding administrationof ripretinib until the patient has less than or equal to Grade 1palmer-plantar erythrodysesthesia syndrome or baseline; b) if thepatient recovers from the palmer-plantar erythrodysesthesia syndromewithin 7 days of withholding administration, then administering to thepatient 150 mg daily ripretinib or c) if the patient has not recovered,then administering to the patient 100 mg daily ripretinib for at least28 days.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 150 mg daily ripretinib,wherein the patient's tumor has progressed from, or the patient wasintolerant to, a first line administration of imatinib, a second lineadministration of sunitinib, and a third line administration ofregorafenib.

In some embodiments, if the patient suffers from a Grade 3palmer-plantar erythrodysesthesia syndrome upon administration of theripretinib, the method further comprises a) withholding administrationof ripretinib for at least 7 days or until the patient has less than orequal to Grade 1 palmer-plantar erythrodysesthesia syndrome, thenadministering to the patient 100 mg daily (e.g., 100 mg once daily)ripretinib for at least 28 days.

In some embodiments, if the patient suffers from a Grade 2palmer-plantar erythrodysesthesia syndrome upon administration of theripretinib, the method further comprises: a) withholding administrationof ripretinib until the patient has less than or equal to Grade 1palmer-plantar erythrodysesthesia syndrome or baseline; b) if thepatient recovers from the palmer-plantar erythrodysesthesia syndromewithin 7 days of withholding administration, then administering to thepatient 150 mg daily ripretinib or c) if the patient has not recovered,then administering to the patient 100 mg daily ripretinib for at least28 days.

In another embodiment, described herein is a method of treating apatient suffering from an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 150 mg of ripretinib onceor twice daily, wherein the patient's tumor has progressed from, or thepatient was intolerant to, a previous first line administration ofimatinib. In some embodiments, if the patient suffers from Grade 3palmer-plantar erythrodysesthesia syndrome upon administration of theripretinib, the method further comprises a) withholding administrationof ripretinib for at least 7 days or until the patient has less than orequal to Grade 1 palmer-plantar erythrodysesthesia syndrome, thenadministering to the patient 100 mg daily (e.g., 100 mg once daily)ripretinib for at least 28 days. In some embodiments, if the patientsuffers from Grade 3 palmer-plantar erythrodysesthesia syndrome uponadministration of the ripretinib, the method further comprises a)withholding administration of ripretinib for at least 7 days or untilthe patient has less than or equal to Grade 1 palmer-plantarerythrodysesthesia syndrome, then administering to the patient 100 mgdaily (e.g., 100 mg once daily) ripretinib for at least 28 days. In someembodiments, if the patient suffers from Grade 2 palmer-plantarerythrodysesthesia syndrome upon administration of the ripretinib, themethod further comprises: a) withholding administration of ripretinibuntil the patient has less than or equal to Grade 1 palmer-plantarerythrodysesthesia syndrome or baseline; b) if the patient recovers fromthe palmer-plantar erythrodysesthesia syndrome within 7 days ofwithholding administration, then administering to the patient 150 mgdaily ripretinib or c) if the patient has not recovered, thenadministering to the patient 100 mg daily ripretinib for at least 28days. In some embodiments, if the patient suffers from a Grade 3 adversedisorder selected from arthralgia or myalgia upon administration of theripretinib, the method further comprises: a) withholding administrationof ripretinib until the patient has less than or equal to Grade 1adverse disorder, then administering to the patient 100 mg daily (e.g.,100 mg once daily) ripretinib for at least 28 days. In some embodiments,if the patient suffers from Grade 3 hypertension upon administration ofthe ripretinib, the method further comprises withholding administrationof ripretinib until the patient's blood pressure is controlled, and ifthe patient has less than or equal to Grade 1 blood pressure is,administering to the patient 150 mg daily ripretinib, or if the patienthas more than Grade 1 blood pressure, administering 100 mg daily (e.g.,100 mg once daily) ripretinib.

In another embodiment, described herein is a method for achieving atleast 5 months of progression free survival as determined by mRECIST 1.1in a patient having an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100, 150 200, or 300 mgof ripretinib daily or twice daily for at least 28 days. In someembodiments, the patient has been administered at least one previouskinase inhibitor. In some embodiments, the patient has been administeredat least three previous kinase inhibitors. In some embodiments, the atleast one previous kinase inhibitor is imatinib. In some embodiments,comprising orally administering to the patient 100, 150 or 200 mg ofripretinib daily or twice daily for at least 4 months.

In another embodiment, described herein is a method for achieving atleast 5 months of progression free survival as determined by mRECIST 1.1in a patient having an advanced gastrointestinal stromal tumor,comprising orally administering to the patient 100, 150, or 200 mg ofripretinib daily or twice daily for at least 28 days. In someembodiments, the patient has been administered at least one previouskinase inhibitor. In some embodiments, the patient has been administeredat least three previous kinase inhibitors. In some embodiments, the atleast one previous kinase inhibitor is imatinib. In some embodiments,comprising orally administering to the patient 100, 150, or 200 mg ofripretinib daily or twice daily for at least 4 months.

In another embodiment, descried herein is a method of treating a patientsuffering from Grade 3 palmer-plantar erythrodysesthesia syndrome whilebeing administered 150 mg ripretinib daily or twice daily, comprisingwithholding administration of ripretinib for at least 7 days or untilthe patient has less than or equal to Grade 1 palmer-plantarerythrodysesthesia syndrome, then administering to the patient 100 mgdaily (e.g., 100 mg once daily) ripretinib for at least 28 days.

In another embodiment, descried herein is a method of treating a patientsuffering from Grade 2 palmer-plantar erythrodysesthesia syndrome uponadministration of 150 mg ripretinib daily or twice daily, comprising a)withholding administration of ripretinib until the patient has less thanor equal to Grade 1 palmer-plantar erythrodysesthesia syndrome orbaseline; b) if the patient recovers from the palmer-plantarerythrodysesthesia syndrome within 7 days of withholding administration,then administering to the patient 150 mg daily ripretinib or c) if thepatient has not recovered, then administering to the patient 100 mgdaily ripretinib for at least 28 days.

In another embodiment, described herein is a method of treating agastrointestinal stromal tumor in a patient in need thereof, wherein thepatient is being treated concurrently with a CYP3A4 inhibitor, themethod comprising: orally administering to the patient 100 mg or 150 mgof ripretinib, or a pharmaceutically acceptable salt thereof, once ortwice daily, and wherein upon administration of the ripretinib and theCYP3A4 inhibitor, provides an increased ripretinib area under the plasmaconcentration curve (AUC_(0-inf)) of 80% or more in the patient ascompared to administration of ripretinib without concurrent treatment ofthe CYP3A4 inhibitor, and therefore the patient is at higher risk of anadverse event; and monitoring the patient more frequently, as comparedto a patient not being treated with a CYP3A4 inhibitor, for the adverseevent. In some embodiments, if the patient suffers from a Grade 3palmer-plantar erythrodysesthesia syndrome adverse event, the methodfurther comprises a) withholding administration of ripretinib for atleast 7 days or until the patient has less than or equal to Grade 1palmer-plantar erythrodysesthesia syndrome, then administering to thepatient 100 mg daily ripretinib for at least 28 days. In someembodiments, if the patient suffers from Grade 2 palmer-plantarerythrodysesthesia syndrome upon administration of the ripretinib, themethod further comprises: a) withholding administration of ripretinibuntil the patient has less than or equal to Grade 1 palmer-plantarerythrodysesthesia syndrome or baseline; b) if the patient recovers fromthe palmer-plantar erythrodysesthesia syndrome within 7 days ofwithholding administration, then administering to the patient 150 mgdaily ripretinib or c) if the patient has not recovered, thenadministering to the patient 100 mg daily ripretinib for at least 28days. In some embodiments, the CYP3A4 inhibitor is selected from thegroup consisting of itraconazole, ketoconazole, clarithromycin, andindinavir. In some embodiments, the CYP3A4 inhibitor is itraconazole. Insome embodiments, the patient has previously been administered one ormore tyrosine kinase inhibitors, each selected from the group consistingof imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib,vatalanib, crenolanib, and pharmaceutically acceptable salts thereof.

In another embodiment, described herein is a method of treating agastrointestinal stromal tumor in a patient in need thereof, wherein thepatient is being treated concurrently with a proton pump inhibitor, themethod comprising: orally administering to the patient 100 mg or 150 mgof ripretinib, or a pharmaceutically acceptable salt thereof, once ortwice daily, and wherein administration of the ripretinib and protonpump inhibitor to the patient provides no clinically significantdifference in the plasma exposure of ripretinib in the patient ascompared to administration of ripretinib without concurrent treatment ofthe proton pump inhibitor. In some embodiments, the proton pumpinhibitor is selected from the group consisting of pantoprazole,omeprazole, lansoprazole, rabeprazole, esomeprazole, anddexlansoprazole. In some embodiments, the proton pump inhibitor ispantoprazole. In some embodiments, the patient is being treatedconcurrently with 40 mg of the proton pump inhibitor once daily.

In another embodiment, described herein is a method of treating agastrointestinal stromal tumor in a patient in need thereof, the methodcomprising orally administering to the patient 100 mg or 150 mg ofripretinib, or a pharmaceutically acceptable salt thereof, once or twicedaily, wherein the ripretinib is administered to the patient with foodor without food. In some embodiments, the food comprises a high-fat meal(e.g., a high-fat meal described herein).

In some embodiments, the therapeutic efficacy of ripretinib isdetermined by the progression-free survival of the patient afterindependent radiologic review using Response Evaluation Criteria inSolid Tumors (RECIST). In some embodiments, the therapeutic efficacy ofripretinib is determined by the progression-free survival of the patientafter independent radiologic review using modified Response EvaluationCriteria in Solid Tumors (mRECIST). In some embodiments, the therapeuticefficacy of ripretinib is determined by the Objective Response Rate(ORR), Time to Tumor Progression (TTP) or Overall Survival (OS) of thepatient after independent radiologic review using mRECIST. In someembodiments, the therapeutic efficacy of ripretinib is determined by theprogression-free survival of the patient based on investigatorassessment. In some embodiments, the therapeutic efficacy of ripretinibis determined by the quality of life of the patient in accordance withEuropean Organisation for Research and Treatment of Cancer Quality ofLife Questionnaire for Cancer 30-item (EORTC-QLQ-C30) and the EuroQol5-Dimension 5-Level (EQ-5D-5L) questionnaires. In some embodiments, thetherapeutic efficacy of ripretinib is determined by the disease controlrate of the patient. In some embodiments, the therapeutic efficacy ofripretinib is determined by the duration of response of the patient.

After at least one month, two months, e.g., 42 days or more of treatmentwith ripretinib, the patient may have a progression-free survival asmeasured using mRECIST v1.1. As another example, the patient may have aleast a 5 or 6 month progression-free survival as compared to placeboafter at least 4 weeks of daily administration of ripretinib, and/or forexample, after 4 weeks of daily administration of ripretinib,significantly reduced the risk of disease progression or death by 85%.

In some embodiments, the patient has at least one measurable tumorlesion according to modified RECIST Version 1.1 within 21 days prior tothe first dose of ripretinib. In some embodiments, the patient has anon-nodal tumor lesion of greater than or equal to 1.0 cm in the longaxis or greater than or equal to double the slide thickness in the longaxis, within 21 days prior to the first dose of ripretinib.

In some embodiments, the patient's tumor has a KIT exon 9 mutation, aPDGFRA exon 18 mutation, a PDGFRA exon 12 mutation or a PDGFRA exon 18activation loop mutation. For example, the patient's tumor mutation is aPDGFRA D842V mutation.

In some embodiments, the patient's tumor has an imatinib resistant,sunitinib resistant, and/or regorafenib resistant mutation selected fromthe group consisting of a KIT exon 17 activation loop mutation, a KITexon 18 activation loop mutation, a KIT exon 13 mutation, a KIT exon 14mutation, a KIT exon 18 mutation, a PDGFRA exon 12 mutation, a PDGFRAexon 14 mutation, a PDGRFA exon 15 mutation, and a PDGFRA exon 18activation loop mutation. For example, the resistant mutation is aPDGFRA D842V mutation.

In some embodiments, the patient's tumor has a drug resistant mutationselected from the group consisting of KIT exon 13 or 14 mutation, PDGFRAexon 14 or 15 mutation, a KIT 17 or 18 activation loop mutation, and aPDGFRA 18 activation loop mutation. For example, the tumor has a drugresistant KIT exon 17 mutation.

Dose Modifications

Dose modifications may be made in the methods of administeringripretinib described herein as a result of adverse events experienced bythe patient. In some embodiments, the dose modification is a doseinterruption. In some embodiments, the dose modification is a permanentdiscontinuation in dosing. In some embodiments, the dose modification isa dose reduction. In some embodiments, the dose of ripretinibadministered to the patient is reduced from 150 mg once daily, e.g.,three tablets each comprising 50 mg of ripretinib, to 100 mg once daily,e.g., two tablets each comprising 50 mg of ripretinib. In someembodiments, the dose of ripretinib administered to the patient isreduced from 150 mg once daily, e.g., three tablets each comprising 50mg of ripretinib, to 50 mg once daily, e.g., one tablet comprising 50 mgof ripretinib. In some embodiments, the adverse reaction is selectedfrom the group consisting of a hand-foot skin reaction (e.g.,palmar-plantar erythrodysesthesia syndrome), hypertension, arthralgia,and myalgia.

In some embodiments, the adverse event is graded in accordance with theNational Cancer Institute Common Terminology Criteria for AdverseEvents, version 4.03 (e.g., baseline, Grade 1, Grade 2, Grade 3, orGrade 4). In some embodiments, the dose modification is a doseinterruption (e.g., a dose interruption of at least 7 days) as a resultof a Grade 2 adverse event. In some embodiments, dosing resumes at thesame dose level before the dose interruption if the adverse event islowered to Grade 1 or baseline within a first time period (e.g., within7 days). In some embodiments, dosing resumes at a reduced dose levelbefore the dose interruption if the adverse event is lowered to Grade 1or baseline after a first time period (e.g., after 7 days). In someembodiments, the reduced dose level is re-escalated to the dose levelprior to the dose interruption if the adverse event is lowered to Grade1 or baseline after a first time period but is maintained as a Grade 1or baseline adverse event after a second time period (e.g., after 28days). In some embodiments, the dose modification is a dose interruption(e.g., a dose interruption of at least 7 days up to a maximum of 28days) as a result of a Grade 3 adverse event. In some embodiments,dosing is continued at a reduced level after the dose interruption. Insome embodiments, the dose modification is a permanent discontinuationin dosing as a result of a Grade 4 adverse event (e.g., Grade 4hypertension).

A patient can be administered an additional treatment in response to anadverse event or to prevent an adverse event from occurring. In someembodiments, a patient suffering from an adverse dermatologic reaction,e.g., a hand-foot skin reaction, e.g., palmar-plantar erythrodysesthesiasyndrome, is administered a topical composition (e.g., an emollient) totreat the adverse dermatologic reaction. In some embodiments, thepatient is administered the topical composition (e.g., an emollient)based on the severity of the adverse dermatologic reaction, e.g., aGrade 2, Grade 3 adverse dermatologic reaction, e.g., a Grade 1, Grade2, or Grade 3 hand-foot skin reaction, e.g., a Grade 1, Grade 2 or Grade3 palmar-plantar erythrodysesthesia syndrome. In some embodiments, thetopical composition (e.g., an emollient) is administered to the patientduring a dose interruption of ripretinib. In some embodiments, thetopical composition (e.g., an emollient) is administered to the patientcontemporaneously with a dose of ripretinib, e.g., a reduced dose ofripretinib.

A patient can also be administered an additional treatment prior to, orduring administration of ripretinib in accordance with the methodsdescribed herein to prevent or ameliorate an adverse event. In someembodiments, the patient is administered a topical composition (e.g., anemollient) before and/or during ripretinib administration to prevent orameliorate the onset of an adverse dermatologic reaction, e.g., ahand-foot skin reaction, e.g., palmar-plantar erythrodysesthesiasyndrome.

EXAMPLES Example 1. An Open-Label, Randomized Study to Compare theEfficacy of Ripretinib Versus Sunitinib in Patients with Advanced GISTwith Prior Imatinib Therapy

Study Design. Approximately 358 eligible patients will be randomizedinto two cohorts in a 1:1 ratio in which one cohort undergoes continuous42-day cycles of receiving ripretinib dosed at 150 mg daily (179patients) and the other cohort receives sunitinib dosed at 50 mg dailyfor 4 weeks and then 2 weeks off on 42-day cycles (179 patients).

Given the mutation-driven natural history of GIST and the well-describedrelationship between secondary mutations and emergence of resistance tofirst- and second-line TKIs, the results of this study will evaluateripretinib compared with sunitinib as second-line therapy in patientswith GIST following imatinib therapy.

The primary end point of the study is to assess the progression-freesurvival (PFS) of ripretinib by blinded independent central review(BICR) using modified Response Evaluation Criteria in Solid Tumorsversion 1.1 (mRECIST v1.1). The key secondary efficacy end pointsinclude the assessment of ORR by BICR using mRECIST v1.1 and OS.

Statistical Analysis. PFS is defined as the time from randomization tothe date of the first documented progression of disease or death due toany cause and is based on BICR assessment of the primary end point. OSis defined as the time from randomization to the date of death due toany cause. OS and PFS with 95% CI will be summarized using Kaplan-Meiermethodology; point estimates of hazard ratios will be obtained from aCox regression model. Objective response is defined as a CR or PR byBICR assessment using mRECIST v1.1.

Example 2. A Randomized, Double-Blind, Placebo-Controlled,International, Multicenter Study to Evaluate the Safety, Tolerability,and Efficacy of Ripretinib Compared to Placebo in Patients with AdvancedGIST Whose Previous Therapies have Included Imatinib, Sunitinib, andRegorafenib

This study was a randomized (2:1), double-blind, placebo-controlled,international, multicenter study to evaluate the safety, tolerability,and efficacy of ripretinib compared to placebo in 129 patients withadvanced GIST whose previous therapies have included at least imatinib,sunitinib, and regorafenib. Patients were randomized 2:1 to either 150mg of ripretinib or placebo once daily. The primary efficacy endpoint isprogression-free survival (PFS) as determined by independent radiologicreview using modified Response Evaluation Criteria in Solid Tumors(RECIST). Secondary endpoints as determined by independent radiologicreview using modified RECIST include Objective Response Rate (ORR), Timeto Tumor Progression (TTP) and Overall Survival (OS).

Results. This study achieved its primary endpoint of improved PFS asdetermined by blinded independent central radiologic review usingmodified Response Evaluation Criteria in Solid Tumors (RECIST) version1.1.

Ripretinib demonstrated a median PFS of 6.3 months (27.6 weeks) comparedto 1.0 month (4.1 weeks) in the placebo arm and significantly reducedthe risk of disease progression or death by 85% (HR of 0.15, p<0.0001)compared to placebo. PFS rates at 6 months were 51% (95% CI: 39.4,61.4)for ripretinib and 3.2% (95% CI: 0.2,13.8) for placebo. Plots ofsurvival probability with respect to PFS for patients on ripretinib andpatients on placebo are shown in FIG. 1 .

For the key secondary endpoint of objective response rate (ORR), asdetermined by blinded independent central radiologic review usingmodified RECIST version 1.1, ripretinib demonstrated an ORR of 9.4%compared with 0% for placebo (p-value=0.0504), which was notstatistically significant. Ripretinib in this study also showed aclinically meaningful improvement over placebo in terms of the secondaryendpoint overall survival (OS) (median OS 15.1 months vs. 6.6 months,HR=0.36, nominal p-value=0.0004; OS rates at 12 months were 65.4% (95%CI: 51.6,76.1) for ripretinib and 25.9% (95% CI: 7.2,49.9) for placebo);however, because statistical significance was not achieved for ORR, thehypothesis testing of OS was not formally performed. Plots of survivalprobability with respect to OS of patients on ripretinib and patients onplacebo are shown in FIG. 2 . According to the pre-specifiedhierarchical testing procedure of the endpoints, the hypothesis testingof OS cannot be formally conducted unless the test of ORR isstatistically significant. The OS data for the placebo arm includespatients taking placebo who, following progression, were crossed-over toripretinib treatment. Plots illustrating survival probability withrespect to OS in patients on ripretinib, crossed over from placebo toripretinib, and patients without cross-over are shown in FIG. 3 . Plotsand additional data illustrating survival probability with respect toPFS in patients on ripretinib, crossed over from placebo to ripretinib,and patients without cross-over are shown in FIG. 13 . Additionally,more patients receiving ripretinib had stable disease (SD) for 12 weeks(40 [47.1%] vs 2 [4.5%], respectively) and less PD (16 [18.8%] vs 28[63.6%], respectively) than patients on placebo. The large percentage ofpatients receiving ripretinib with stable disease (SD) is notable as theabsence of progression is considered an important marker of therapeuticbenefit in GIST. Unlike many other advanced solid tumors, the absence ofprogression (whether a partial response (PR) or SD) is predictive of PFSand OS benefit in patients with advanced GIST.

Patients that successfully crossed over from placebo had smaller tumorsvs those that did not crossover (median sum of longest diameter oftarget lesions 119.4 mm vs 183.3 mm). In addition, the median age ofthose who crossed over was higher than those who did not cross over(68.0 vs 58.0 years) and none had a baseline Eastern CooperativeOncology Group (ECOG) score of 2, while 3 patients in the group that didnot cross over had an ECOG score of 2. Patients that crossed over had amedian PFS of 20.0 weeks [95% CI, 8.0-NE] vs 27.6 weeks seen in theinitial ripretinib arm and 4.1 weeks seen in the initial placebo arm,respectively. Median OS in patients who crossed over was 11.6 months,vs. 15.1 months in patients initially randomized to ripretinib and 1.8months in patients on placebo who did not crossover. TEAEs during thecrossover period suggest no safety concerns when compared to the safetyprofile of patients initially assigned to ripretinib.

Ripretinib was generally well tolerated and the adverse event resultswere consistent with data from previously presented Phase 1 studyresults. Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurredin 42 (49%) patients on the ripretinib arm compared to 19 (44%) on theplacebo arm. Grade 3 or 4 TEAEs>5% of patients in the ripretinib armwere anemia (9%; n=8), abdominal pain (7%; n=6) and hypertension (7%;n=6). Grade 3 or 4 TEAEs>5% of patients in the placebo arm were anemia(14%; n=6). Table 1 lists TEAEs>15% in the ripretinib arm compared toplacebo.

TABLE 1 Treatment-emergent adverse events for patients administered witheither ripretinib or placebo. Ripretinib 150 mg Treatment EmergentPlacebo Daily Adverse Event (N = 43)⁽¹⁾ (N = 85)⁽¹⁾ Any event 42 (98%)84 (99%) Alopecia  2 (5%) 44 (52%) Fatigue 10 (23%) 36 (42%) Nausea  5(12%) 33 (39%) Abdominal pain 13 (30%) 31 (36%) Constipation  8 (19%) 29(34%) Myalgia  5 (12%) 27 (32%) Diarrhea  6 (14%) 24 (28%) Decreasedappetite  9 (21%) 23 (27%) Palmar-plantar  0 18 (21%) erythrodysesthesiasyndrome Vomiting  3 (7%) 18 (21%) Headache  2 (5%) 16 (19%) Weightdecreased  5 (12%) 16 (19%) Arthralgia  2 (5%) 15 (18%) Blood bilirubinincreased  0 14 (16%) Oedema peripheral  3 (7%) 14 (16%) Muscle spasms 2 (5%) 13 (15%)

In table 1, (1) indicates that the safety population includes 128patients. One patient was randomized to placebo but did not receivestudy drug.

Patient Reported Outcomes

Patient reported outcomes were assessed by EQ-5D-5L, which provides avisual analogue scale (VAS), and EORTC QLQ-C30, which provides physicalfunction and role function scales. The EQ-5D-5L VAS (or EQ-VAS) recordsthe respondent's overall current health on a vertical visual analoguescale and provides a quantitative measure of the patient's perception ofoverall health. These patient outcomes were reported across 28-daycycles of receiving 150 mg QD ripretinib or placebo.

FIG. 5A, FIG. 5B, and FIG. 5C depict patient report outcome by EQ-VASshowing the visual scale used to assess scores (FIG. 5A), score changesfrom baseline (FIG. 5B) and corresponding patient percentagedistributions (FIG. 5C). The EQ-VAS score improved on average 3.7 frombaseline to Cycle 2, Day 1 (C2D1) among patients taking ripretinib incontrast to placebo patients who saw on average, a decline from baselineto C2D1 of 8.9 (p=0.004). 70 patients were receiving ripretinib and 32were receiving placebo.

The EORTC QLQ-C30 is an assessment of function and symptoms of therapyby cancer patient, and is not specific to any cancer. The EORTC QLQ-C30is a 30-question plus one global health status, including 5 functionalscales, 3 symptom scales and a global health status.

FIG. 6A, FIG. 6B, and FIG. 6C depict EORTC QLQ-C30 physical functionquestions (FIG. 6A), patient score changes from baseline in response(FIG. 6B) and corresponding patient percentage distributions (FIG. 6C).Physical function scores improved on average 1.6 from baseline to C2D1among patients taking ripretinib in contrast to placebo patients who sawon average, a decline from baseline to C2D1 of 8.9 (p=0.004). 71patients were receiving ripretinib and 32 were receiving placebo.

FIG. 7A, FIG. 7B, and FIG. 7C depict EORTC QLQ-C30 role functionquestions (FIG. 7A) and patient score changes from baseline in response(FIG. 7B) and corresponding patient percentage distributions (FIG. 7C).Role function score improved on average 3.5 from baseline to C2D1 amongpatients taking ripretinib in contrast to placebo patients who saw onaverage, a decline from baseline to C2D1 of 17.1 (p=0.001). 70 patientswere receiving ripretinib and 32 were receiving placebo.

FIG. 8A and FIG. 8B depict patient score changes from baseline (FIG. 8A)and corresponding patient percentage distributions (FIG. 8B) in responseto Question C29 of EORTC QLQ-C30 (“How would you rate your overallhealth during the past week?”) from a scale of 1 (“Very poor”) to 7(“Excellent”). There was a 0.20 improvement in C29 score in theripretinib group compared to a 0.78 decrease in the placebo group(p=0.001). 70 patients were receiving ripretinib and 32 were receivingplacebo.

FIG. 9A and FIG. 9B depict patient score changes from baseline (FIG. 9A)and corresponding patient percentage distributions (FIG. 9B) in responseto Question C30 of EORTC QLQ-C30 (“How would you rate your overallquality of life during the past week?”) from a scale of 1 (“Very poor”)to 7 (“Excellent”). There was a 0.28 improvement in score in theripretinib group compared to a 0.76 decrease in the placebo group(p=0.001). 70 patients were receiving ripretinib and 32 were receivingplacebo.

FIG. 10 depicts mean changes in baseline scores in EQ-VAS across varioustime points, from Cycle 1, Day 15 up to Cycle 15, Day 1 of theintention-to-treat population. FIG. 11A and FIG. 11B depict mean changesin baseline scores in EORTC QLQ-C30 role function and EORTC QLQ-C30physical function, respectively, across various time points, from Cycle1, Day 15 up to Cycle 15, Day 1 of the intention-to-treat population.FIG. 12A and FIG. 12B depict mean changes in baseline scores in EORTCQLQ-C30 question C29 response and EORTC QLQ-C30 question C30 response,respectively, across various time points, from Cycle 1, Day 15 up toCycle 15, Day 1 of the intention-to-treat population.

Open-Label Phase and Dose Escalation

Patients whose disease progressed during the double blind phase of thestudy were escalated to 150 mg BID ripretinib, continued at the 150 mgQD dose, or discontinued in an open label-phase of the study. Table 8shows a comparison of patients that received 150 mg QD ripretinib at thedata cutoff time point of the double blind phase and the data cutofftime point of the open-label phase. The data in Table 8 suggest thatdata cut 9 months after the primary double-blind analysis has shownimprovement in mOS and a similar mPFS in the ripretinib arm.

In the study, at least 31 patients dose escalated to 150 mg BIDripretinib in an open-label phase upon disease progression. PFS studiesin the double-blind and open-label periods for these patients aredepicted in FIG. 14A and FIG. 14B, respectively, with FIG. 14C depictingmedian PFS data.

Wild Type (KIT and PDGFRA) Mutations

PFS data among patients with wild-type KIT or PDGFRA mutations werefurther evaluated at 150 mg ripretinib QD. PFS data of patients withthese wild-type KIT and PDGFRA mutations are shown in FIG. 15 .

Additional Mutational Analyses

Progression free survival PFS and overall survival (OS) data based onpatients with a primary Exon 11 mutation or patients with a non-Exon 11mutation are shown in FIGS. 16A (PFS) and 16B (OS) at 150 mg ripretinibQD. The data show that, regardless of primary mutation, whether aprimary Exon 11 or a non-Exon 11 primary mutation, GIST patients derivesimilar benefit from ripretinib over placebo.

Progression free survival PFS and overall survival (OS) data based onpatients with a primary Exon 11 mutation or those with a primary Exon 9mutation are shown in FIGS. 17A (PFS) and 17B (OS) at 150 mg ripretinibQD. The data show that, Regardless of primary mutation, both Exon 11 andExon 9 GIST patients derive a benefit from ripretinib over placebo.

Furthermore, progression free survival PFS and overall survival (OS)data based on patients with a primary Exon 11 mutation, or a primaryExon 9 mutation, or other mutations, and wild type (KIT and PDGFRA) areshown in FIGS. 18A (PFS) and 19B (OS) at 150 mg ripretinib QD.

PFS studies for patients with certain primary mutations (Exon 9 or Exon11) who dose escalated to 150 mg BID ripretinib are shown in FIGS. 19Aand 19B for the double-blind and open-label periods, respectively.

Additionally, FIG. 20 shows exemplary progression free survival data forpatients with other KIT mutations and PGDFR mutations in the study ofExample 2 at 150 mg ripretinib QD.

FIGS. 26A-D depicts an exemplary comparison of PFS of patient subgroupswith Exon 9 (FIG. 26A), Exon 11 (FIG. 26B), Exon 13 (FIG. 26C), or Exon17 (FIG. 26D) KIT mutations. This exemplary data show that ripretinibshowed PFS benefit in all assessed patient subgroups compared toplacebo.

Example 3. Results for a Clinical Study of Ripretinib in Patients withSecond-Line Through Fourth-Line Plus GIST

Results. Data from 178 GIST patients receiving ripretinib at dosesof >100 mg daily are noted in Table 2. The table includesinvestigator-assessed objective response rate (ORR) by best response,disease control rate (DCR) and median progression free survival (mPFS),all of which were determined by Response Evaluation Criteria in SolidTumors (RECIST) version 1.1.

TABLE 2 Results/clinical study of ripretinib Objective Response Rate byBest Response Disease Median Includes Control Progression UnconfirmedRate Free Censored Mean (Confirmed at 3 Survival Patients Treatment Lineof Therapy⁽¹⁾ Only) Months (mPFS) for mPFS Duration⁽²⁾⁽ ³⁾ Second-Line(n = 37) 30% (22%) 81% 42 weeks 38% 43 weeks Third-Line (n = 31) 23%(13%) 80% 40 weeks 32% 48 weeks Fourth-Line (n = 60) 15% (8%) 73% 30weeks 30% 49 weeks ≥Fourth-Line 11% (7%) 66% 24 weeks 22% 41 weeks (n =110)⁽⁴⁾

In Table 2, (1) indicates overall number of patients (n=178) remains thesame as prior data presented at ESMO 2018; based on additional datacleaning, one patient from each of 2^(nd) line and 4^(th)/>4^(th) linewere reclassified as 3^(rd) line patients; (2) refers to mediantreatment durations were: 2^(nd) line=44 weeks, 3^(rd) line=48 weeks,4^(th) line=46 weeks and ≥4^(th) line=29 weeks; (3) refers to including60 patients who elected for intra-patient dose escalation from 150 mg QDto 150 mg BID; and (4) refers to the number of patients including 60patients from 4^(th) line.

Ripretinib was generally well tolerated and the updated adverse eventswere consistent with previously presented Phase 1 data in patients withGIST. Grade 3 or 4 treatment-emergent adverse events (TEAEs) in >5% ofpatients were lipase increased (18%; n=33), anemia (11%; n=20),hypertension (7%; n=13) and abdominal pain (6%; n=11). 13% of patients(n=24) experienced TEAEs leading to study treatment discontinuation, 17%of patients (n=31) experienced TEAEs leading to dose reduction and 49%of patients (n=88) had TEAEs leading to study drug interruption. Table 3lists TEAEs>10% for GIST patients treated with ≥100 mg of ripretinibdaily.

TABLE 3 Treatment-emergent adverse events for patients administered with100 mg of ripretinib daily. GIST PATIENTS @ ≥ 100 MG DAILY TreatmentEmergent Adverse Events (TEAEs) >10% Alopecia 102 (57%)  0 (0%) 102(57%) Fatigue  94 (53%)  4 (2%)  98 (55%) Myalgia  79 (44%)  0 (0%)  79(44%) Nausea  77 (43%)  1 (1%)  78 (44%) Palmar-plantar  71 (40%)  1(1%)  72 (40%) erythrodysaesthesia syndrome Constipation  67 (37%)  0(0%)  67 (37%) Decreased appetite  60 (34%)  2 (1%)  62 (35%) Diarrhea 50 (28%)  3 (2%)  53 (30%) Weight decreased  51 (29%)  1 (1%)  52 (29%)Lipase increased  18 (10%) 33 (18%)  51 (29%) Muscle spasms  47 (26%)  0(0%)  47 (26%) Abdominal pain  33 (18%) 11 (6%)  44 (25%) Vomiting  42(24%)  2 (1%)  44 (25%) Arthralgia  40 (22%)  0 (0%)  40 (22%) Anemia 18 (10%) 20 (11%)  38 (21%) Hypertension  25 (14%) 13 (7%)  38 (21%)Cough  37 (21%)  0 (0%)  37 (21%) Dry skin  37 (21%)  0 (0%)  37 (21%)Dyspnea  32 (18%)  4 (2%)  36 (20%) Headache  33 (18%)  1 (1%)  34 (19%)Back Pain  30 (17%)  2 (1%)  32 (18%) Dizziness  29 (16%)  0 (0%)  29(16%) Rash  27 (15%)  0 (0%)  27 (15%) Hypokalaemia  21 (12%)  5 (3%) 26 (15%) Hypopho sphataemia  17 (10%)  8 (5%)  25 (14%) Actinickeratosis  25 (14%)  0 (0%)  25 (14%) Blood bilirubin increase  16 (9%) 5 (3%)  21 (12%) Amylase increased  19 (11%)  2 (1%)  21 (12%) Insomnia 21 (12%)  0 (0%)  21 (12%) Seborrhoeic keratosis⁽²⁾  21 (12%)  0 (0%) 21 (12%) Urinary tract infection  16 (9%)  4 (2%)  20 (11%) Dysgeusia 20 (11%)  0 (0%)  20 (11%) Pain in extremity  18 (10%)  1 (1%)  19(11%) Blood creatine phosphokinase  13 (7%)  5 (3%)  18 (10%) increasedUpper respiratory tract infection  18 (10%)  0 (0%)  18 (10%) Rashmaculo-papular  18 (10%)  0 (0%)  18 (10%) Hypomagnesaemia  18 (10%)  0(0%)  18 (10%) Pruritus  18 (10%)  0 (0%)  18 (10%) Skin papilloma⁽²⁾ 17 (10%)  0 (0%)  17 (10%) Vision blurred  17 (10%)  0 (0%)  17 (10%)

In table 3, (1) refers to including one patient that only participatedin the food effect portion of the Phase 1 study; and (2) indicates thatdermatology skin exams were implemented to better evaluate skin lesions.

Example 4. Results for a Clinical Study of 150 mg QD RipretinibAdministered to Patients with Second-Line Through Fourth-Line Plus GIST

Efficacy and safety results from the escalation and expansion phases ofa phase 1 study for patients with GIST treated at ripretinib 150 mg QDas the starting dose in 28-day cycles are presented. Local,investigator-assessed Response Evaluation Criteria in Solid Tumors(RECIST 1.1) response assessments were performed every 2 cycles, andpatients in the expansion cohorts who progressed per RECIST 1.1 wereallowed to dose escalate to 150 mg BID.

142 patients with GIST in the escalation and expansion phases weretreated at 150 mg QD dose. Number of patients by line of therapy were asfollows: 31 2^(nd) line, 28 3^(rd) line, and 83≥4^(th) line patients.135 patients (95.1%) had KIT-mutant GIST, and 7 patients (4.9%) hadPDGFRA-mutant GIST.

Results on the efficacy by line of therapy in patients with GISTreceiving ripretinib 150 mg QD are presented in Table 4. For example,the confirmed-only complete response (CR), partial response (PR), stabledisease, and progressive disease are presented in Table 4. The objectiveresponse rate data in Table 4 relates to the proportion of patients withCR+PR. The median PFS data in Table 4 refers to progression-freesurvival per investigator assessment, by line of therapy. PFS plots byline of therapy are also shown in FIG. 4 .

TABLE 4 Efficacy by line of therapy in patients with GIST receivingripretinib 150 mg QD. 2^(nd) Line 3^(rd) Line 24th Line Parameters (n =31) (n = 28) (n = 83) Best response (confirmed only), n (%) CR  0  0  0PR  6 (19.4)  4 (14.3)  6 (7.2) Stable disease 21 (67.7) 18 (64.3) 49(59.0) Progressive disease  4 (12.9)  6 (21.4) 22 (26.5) Not evaluable 0  0  1 (1.2) No response assessment  0  0  5 (6.0) ORR, n (95% CI)19.4 (7.5, 14.3 (4.0, 7.2 (2.7, 37.5) 32.7) 15.1) Duration oftreatment^(a) Mean, weeks (SD) 56.1 (34.24) 57.5 (32.95) 44.9 (36.58)Median, weeks 64 51 29 Min, Max  4, 132  8, 124  0.1, 140 Duration ofresponse n  6  4  6 Number of events  3  1  3 Median, weeks 80 NE 76.195% CI 24.7, 80.0 52.1, NE 24.1, NE PFS Number of censored  8  6 12patients Median, weeks 46.4 36.3 23.9 95% CI 24.0, 60.0 23.9, 48.4 15.9,24.3In Table 4: ^(a)64 subjects escalated to 150 mg BID among patients withGIST in the 150 mg QD dose group. CI, confidence interval; CR, completeresponse; NE, not estimable; ORR, objective response rate; PFS,progression-free survival; PR, partial response; SD, standard deviation.Local (investigator) response assessment.

In subjects dose escalated to 150 mg BID, PFS before (PFS1) and after(PFS2) dose escalation was evaluated and is shown in FIGS. 25A and 25B,respectively. The data support that, regardless of line of therapy,patients received additional clinical benefit by investigator assessmentafter dose escalation to 150 mg BID.

Mutational Analysis

FIG. 27 shows PFS data of exemplary second and third-line patients withExons 9, 11, 13, or 17 KIT mutations. The data show that, in second andthird line populations, patients with such various KIT mutations havecomparable PFS.

Example 5. Protocol for Dose Modification of Ripretinib as a Result ofAdverse Reactions

If dose modifications of ripretinib are required due to adversereactions, the following protocol will be applied: reduce the dose in 50mg (one tablet) increments; the lowest recommended dose of ripretinib is50 mg once daily. Ripretinib dosage reductions for adverse reactions aresummarized in Table 5.

TABLE 5 Recommended Dose Reduction for Adverse Reactions Dose Level DoseRecommended starting dose 150 mg once daily First dose reduction Reduceto 100 mg once daily Second dose reduction Reduce to 50 mg once daily(lowest recommended dose)

Dosing will be reduced, interrupted, or discontinued for certaintoxicities. See Table 6 for dose modification guidelines.

TABLE 6 Recommended Dose Modifications for ripretinib Adverse ReactionSeverity^(a) Dosage Modifications Hand-foot skin reaction Grade 2Interrupt ripretinib for at least 7 days. (HFSR) [palmar-plantar If theevent returns to Grade 1 or baseline erythrodysesthesia within 7 days,resume ripretinib at the syndrome (PPES)] same dose level. If the eventreturns to Grade 1 or baseline after 7 days, resume ripretinib at areduced dose level (see Table 5). If after a dose reduction, the eventis maintained at Grade 1 or baseline for at least 28 days, considerre-escalating ripretinib by 1 dose level (see Table 5). If this is arecurrence, after event returns to Grade 1 or baseline, resumeripretinib at a reduced dose level (see Table 5) regardless of time toimprovement. Grade 3 Interrupt ripretinib for at least 7 days or untilthe event returns to Grade 1 or baseline (maximum 28 days). Resumeripretinib at a reduced dose level (see Table 5). If after a dosereduction the event is maintained at Grade 1 or baseline for at least 28days of dosing, consider re- escalating ripretinib by 1 dose level (seeTable 5). Hypertension Grade 3 Medically manage hypertension to achievenormal blood pressure If symptomatic hypertension, withhold ripretiniband treat hypertension. Resume ripretinib at the same dose level aftersymptoms have resolved. If blood pressure is not controlled with medicalmanagement, reduce ripretinib to the next dose level (see Table 5). IfGrade 3 hypertension recurs despite ripretinib dose reduction andmedical management, reduce ripretinib to the lowest recommended dose of50 mg once daily. Grade 4 Discontinue ripretinib permanently.Life-threatening consequences (e.g., malignant hypertension, transientor permanent neurologic deficit, hypertensive crisis) Arthralgia/MyalgiaGrade 2 Interrupt ripretinib for at least 7 days. If the event returnsto Grade 1 or baseline within 7 days, resume ripretinib at the same doselevel. If the event returns to Grade 1 or baseline after 7 days, resumeripretinib at a reduced dose level (see Table 5). If after a dosereduction, the event is maintained at Grade 1 or baseline for at least28 days of dosing, consider re- escalating ripretinib by 1 dose level(see Table 5). If this is a recurrence, after event returns to Grade 1or baseline, resume ripretinib at a reduced dose level (see Table 5)regardless of time to improvement. Grade 3 Interrupt ripretinib for atleast 7 days or until the event returns to Grade 1 or baseline (maximum28 days). Resume ripretinib at a reduced dose level (see Table 5). Ifafter a dose reduction the event is maintained at Grade 1 or baselinefor at least 28 days of dosing, consider re- escalating ripretinib by 1dose level (see Table 5). Other adverse reactions Grade 3 or Interruptripretinib until toxicity resolves higher toxicity to Grade 1 orbaseline (maximum 28 considered days). related to If the event returnsto Grade 1 or treatment baseline, resume ripretinib at a reduced doselevel (see Table 5). If the reduced dose is tolerated without recurrenceof the event for at least 28 days, consider re-escalating ripretinib tothe prior dose level (see Table 5). If Grade 3 or higher toxicityrecurs, discontinue ripretinib. BP = blood pressure; DBP = diastolicblood pressure; SBP = systolic blood pressure ^(a)Graded per NationalCancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) version 4.03

Example 6. Safety of Ripretinib and Impact of Alopecia andPalmar-Plantar Erythrodysesthesia (PPES) on Patient-Reported Outcomes

The safety of ripretinib and the impact of alopecia and palmar-plantarerythrodysesthesia (PPES) on patient-reported outcomes (PROs) ofpatients treated in the study described in Example 2 herein aredescribed. Ripretinib had a favorable overall safety and tolerabilityprofile in the trial of Example 2. When stratified by alopecia and PPES,patient reported assessments of function, overall health, and overallquality of life were maintained over time. For both alopecia and PPES,onset and maximum severity occurred almost simultaneously, indicatingthat these events generally did not progressively worsen. Overall, theseresults suggest that alopecia and PPES are manageable and thatripretinib treatment offsets any negative impact associated with theseAEs.

Patient reported outcomes (PROs) were assessed with questions from theEuroQol 5D (EQ 5D 5L) and the European Organization for the Research andTreatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30).

Generalized estimating equation (GEE) models were used in statisticalanalyses in which: Repeated measures models across visits where theoutcome was 1 of the 5 PROs; models were built only for ripretinibpatients; for alopecia patients, cycles 1 and 2 were excluded to accountfor median time of alopecia onset; covariates were sex, alopecia/PPES(yes/no), and Eastern Cooperative Oncology Group (ECOG) score atbaseline; and when there was no end date for the AE, it was codedconservatively as having extended to the last visit of the double blindperiod.

In the ripretinib arm, the most common treatment-emergent adverse event(TEAE) was alopecia (51.8%) and the most common grade 3/4 TEAE wasanemia (9.4%). The highest severity classification for alopecia is grade2; therefore, no patients in either arm had grade 3/4 alopecia. Alopeciawas slightly more common in femalesys males in the ripretinib arm (56.8%vs 43.2%). In the ripretinib arm, 21.2% of patients reported PPES; nopatients had grade 3 PPES (grade 3 is the highest severityclassification for PPES). There were no serious adverse events ofalopecia or PPES reported. Within the ripretinib arm, 7.1%, 23.5%, and5.9% of patients experienced a TEAE leading to dose reduction, doseinterruption, or death, respectively, compared with 2.3%, 20.9%, and23.3% in the placebo arm. In patients receiving ripretinib, the medianworst grade of alopecia occurred very shortly after the median firstappearance (FIG. 21 ). The median first appearance and worst grade ofPPES occurred simultaneously in patients receiving ripretinib (FIG. 21).

Table 7 shows a GEE analysis summary of the association between alopeciaand PPES with the 5 PRO measures in patients taking ripretinib. In arepeated measures analysis, there was a trend toward an improvement ofthe 5 PROs among patients with alopecia (Table 7). The presence ofalopecia was associated with better self-reported overall quality oflife (Table 7). This was statistically significant at P<0.01, but didnot exceed the threshold for meaningful change. There was no associationbetween PPES and the 5 PRO measures (Table 7).

TABLE 7 GEE analysis summary of the association between alopecia andPPES with the 5 PRO measures in patients taking ripretinib. Mean P-valueMean Confidence from Estimate Limit ChiSq Alopecia EORTC-QLQ-C30 Overallhealth 0.17 (−0.10, 0.44) 0.2222 Overall quality of life 0.35   (0.03,0.67) 0.0313 Physical function 3.17 (−0.29, 6.64) 0.0729 Role function4.50 (−2.87, 11.87) 0.2310 EQ-5D-5L VAS 3.01 (−0.64, 6.67) 0.1062 PPESEORTC-QLQ-C30 Overall health 0.06 (−0.29, 0.41) 0.7457 Overall qualityof life 0.12 (−0.26, 0.50) 0.5368 Physical function 3.03 (−0.92, 6.99)0.1325 Role function 2.83 (−5.52, 11.17) 0.5070 EQ-5D-5L VAS 1.65(−2.11, 5.41) 0.3903

Longitudinal graphs out to Cycle 10, Day 1 demonstrate similar trends inmean change from baseline for the 5 PROs for patients receivingripretinib that developed alopecia or PPES and those that did not (FIGS.22A, 22B, 22C, 22D, 23A, 23B, 23C, 23D, 24A, and 24B).

TABLE 8 Comparison of double blind and open label data cut time periods.Ripretinib Ripretinib (N = 85) (N = 85) Double-blind cut Open-label cutProgression-Free Survival by BICR Number of events (%)   51 (60)   64(75) Progressive disease   46 (54)   58 (68) Deaths   5 (6)   6 (7)Median PFS (months) (95% CI)  6.3 (4.6, 6.9)  6.3 (4.6, 8.1) Hazardratio (95% CI) 0.15 (0.09, 0.25) 0.16 (0.10, 0.27) p-value <0.0001<0.0001* Overall Response Rate by BICR Overall Response Rate (%)   9 12(95% CI) (4.2, 18) (5.8, 20.6) p-value   0.0504   0.0156* OverallSurvival Number of deaths (%)   26 (31)   38 (45) Median OS (months)(95% CI)   15 (12, 15) Not Reached (13, NE) Hazard ratio (95%CI)/p-value 0.36 (0.21, 0.62)/0.0004* 0.43 (0.26, 0.69)/0.0014* ExposureMean in the double blind period 5.6 7.6 (months)

Example 7. Studies of Ripretinib and Compound A with Strong CYP3AInhibitors

Coadministration of 150 mg QD ripretinib with a strong CYP3A inhibitorincreased the exposure of ripretinib and its active metabolite (CompoundA), which may increase the risk of adverse reactions. Coadministrationof ripretinib with itraconazole (a strong CYP3A inhibitor and also aP-gp inhibitor) increased ripretinib C_(max) by 36% and AUC_(0-inf) by99% and also increased Compound A AUC_(0-inf) by 99% with no change inits C_(max).

Example 8. Studies of Ripretinib with a Proton-Pump Inhibitor

The effect of a proton-pump inhibitor on the exposure of ripretinib wasevaluated. No clinically significant differences in the plasma exposureto ripretinib and Compound A were observed when ripretinib wascoadministered with pantoprazole, a proton-pump inhibitor. Althoughripretinib has pH-dependent solubility, concomitant administration of 40mg QD pantoprazole with 150 mg QD ripretinib did not affect ripretinibexposure.

Example 9. Studies of Food Effect on Ripretinib and Compound A Exposure

The effect of a high-fat breakfast on ripretinib and Compound A exposurewas evaluated. A high fat meal consisted of approximately 150, 250, and500-600 calories from protein, carbohydrate, and fat, respectively.Following administration of ripretinib with a high-fat meal at a 150 mgdose, ripretinib AUC_(0-24 h) and C_(max) were higher by 30% and 22%,respectively. For the metabolite Compound A, AUC_(0-24 h) and C_(max)were higher by 47% and 66%, respectively. The food effect is notconsidered to be clinically significant based on exposure-responseanalysis. Therefore, ripretinib may be taken with or without food atapproximately same time each day.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

The invention claimed is:
 1. A method of treating a patient sufferingfrom a Grade 3 adverse reaction while being administered 150 mgripretinib daily for treatment of gastrointestinal stromal tumors,comprising: withholding administration of ripretinib for a maximum of 28days until the adverse reaction resolves to Grade 1 or baseline; thenadministering to the patient 100 mg daily ripretinib for at least 28days.
 2. The method of claim 1, wherein, if after 28 days of 100 mgdaily dosing the adverse reaction in the patient is maintained at Grade1 or baseline, the method comprises administering 150 mg dailyripretinib to the patient.